Original Research published: 16 November 2015 doi: 10.3389/fimmu.2015.00581
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Satoshi Uchiyama1† , Simon Döhrmann1† , Anjuli M. Timmer1 , Neha Dixit2 , Mariam Ghochani3 , Tamara Bhandari1 , John C. Timmer4 , Kimberly Sprague1 , Juliane Bubeck-Wardenburg5 , Scott I. Simon2 and Victor Nizet1,6* Department of Pediatrics, University of California San Diego, La Jolla, CA, USA, 2 Department of Biomedical Engineering, University of California Davis, Davis, CA, USA, 3 Department of Biological Sciences, San Diego State University, San Diego, CA, USA, 4 Department of Pharmacology, University of California San Diego, La Jolla, CA, USA, 5 Department of Pediatrics, University of Chicago, Chicago, IL, USA, 6 Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA 1
Edited by: Inka Sastalla, National Institutes of Health, USA Reviewed by: Francis Alonzo, Loyola University Chicago, USA Stephen B. Beres, Houston Methodist Research Institute, USA *Correspondence: Victor Nizet [email protected] † Satoshi Uchiyama and Simon Döhrmann have contributed equally to this work.
Specialty section: This article was submitted to Microbial Immunology, a section of the journal Frontiers in Immunology Received: 01 September 2015 Accepted: 30 October 2015 Published: 16 November 2015 Citation: Uchiyama S, Döhrmann S, Timmer AM, Dixit N, Ghochani M, Bhandari T, Timmer JC, Sprague K, Bubeck-Wardenburg J, Simon SI and Nizet V (2015) Streptolysin O Rapidly Impairs Neutrophil Oxidative Burst and Antibacterial Responses to Group A Streptococcus. Front. Immunol. 6:581. doi: 10.3389/fimmu.2015.00581
Group A Streptococcus (GAS) causes a wide range of human infections, ranging from simple pharyngitis to life-threatening necrotizing fasciitis and toxic shock syndrome. A globally disseminated clone of M1T1 GAS has been associated with an increase in severe, invasive GAS infections in recent decades. The secreted GAS pore-forming toxin streptolysin O (SLO), which induces eukaryotic cell lysis in a cholesterol-dependent manner, is highly upregulated in the GAS M1T1 clone during bloodstream dissemination. SLO is known to promote GAS resistance to phagocytic clearance by neutrophils, a critical first element of host defense against invasive bacterial infection. Here, we examine the role of SLO in modulating specific neutrophil functions during their early interaction with GAS. We find that SLO at subcytotoxic concentrations and early time points is necessary and sufficient to suppress neutrophil oxidative burst, in a manner reversed by free cholesterol and anti-SLO blocking antibodies. In addition, SLO at subcytotoxic concentrations blocked neutrophil degranulation, interleukin-8 secretion and responsiveness, and elaboration of DNA-based neutrophil extracellular traps, cumulatively supporting a key role for SLO in GAS resistance to immediate neutrophil killing. A non-toxic SLO derivate elicits protective immunity against lethal GAS challenge in a murine infection model. We conclude that SLO exerts a novel cytotoxic-independent function at early stages of invasive infections (
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Satoshi Uchiyama1† , Simon Döhrmann1† , Anjuli M. Timmer1 , Neha Dixit2 , Mariam Ghochani3 , Tamara Bhandari1 , John C. Timmer4 , Kimberly Sprague1 , Juliane Bubeck-Wardenburg5 , Scott I. Simon2 and Victor Nizet1,6* Department of Pediatrics, University of California San Diego, La Jolla, CA, USA, 2 Department of Biomedical Engineering, University of California Davis, Davis, CA, USA, 3 Department of Biological Sciences, San Diego State University, San Diego, CA, USA, 4 Department of Pharmacology, University of California San Diego, La Jolla, CA, USA, 5 Department of Pediatrics, University of Chicago, Chicago, IL, USA, 6 Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA 1
Edited by: Inka Sastalla, National Institutes of Health, USA Reviewed by: Francis Alonzo, Loyola University Chicago, USA Stephen B. Beres, Houston Methodist Research Institute, USA *Correspondence: Victor Nizet [email protected] † Satoshi Uchiyama and Simon Döhrmann have contributed equally to this work.
Specialty section: This article was submitted to Microbial Immunology, a section of the journal Frontiers in Immunology Received: 01 September 2015 Accepted: 30 October 2015 Published: 16 November 2015 Citation: Uchiyama S, Döhrmann S, Timmer AM, Dixit N, Ghochani M, Bhandari T, Timmer JC, Sprague K, Bubeck-Wardenburg J, Simon SI and Nizet V (2015) Streptolysin O Rapidly Impairs Neutrophil Oxidative Burst and Antibacterial Responses to Group A Streptococcus. Front. Immunol. 6:581. doi: 10.3389/fimmu.2015.00581
Group A Streptococcus (GAS) causes a wide range of human infections, ranging from simple pharyngitis to life-threatening necrotizing fasciitis and toxic shock syndrome. A globally disseminated clone of M1T1 GAS has been associated with an increase in severe, invasive GAS infections in recent decades. The secreted GAS pore-forming toxin streptolysin O (SLO), which induces eukaryotic cell lysis in a cholesterol-dependent manner, is highly upregulated in the GAS M1T1 clone during bloodstream dissemination. SLO is known to promote GAS resistance to phagocytic clearance by neutrophils, a critical first element of host defense against invasive bacterial infection. Here, we examine the role of SLO in modulating specific neutrophil functions during their early interaction with GAS. We find that SLO at subcytotoxic concentrations and early time points is necessary and sufficient to suppress neutrophil oxidative burst, in a manner reversed by free cholesterol and anti-SLO blocking antibodies. In addition, SLO at subcytotoxic concentrations blocked neutrophil degranulation, interleukin-8 secretion and responsiveness, and elaboration of DNA-based neutrophil extracellular traps, cumulatively supporting a key role for SLO in GAS resistance to immediate neutrophil killing. A non-toxic SLO derivate elicits protective immunity against lethal GAS challenge in a murine infection model. We conclude that SLO exerts a novel cytotoxic-independent function at early stages of invasive infections (
